Large international study identifies genetic predisposition to lung cancer

In a paper published in the April 3 edition of Nature*, a worldwide consortium of investigators present a major breakthrough for understanding the genetic basis of lung cancer. The international team of investigators have uncovered for the first time an important genetic region that is associated with lung cancer risk and helps to understand the process by which tobacco smoking can cause this cancer. The findings are based on the largest genetic study of lung cancer ever conducted, involving over 10,000 people from 18 countries, about half of whom had lung cancer, and was led by the International Agency for Research on Cancer based in Lyon, France, and two leading French institutes : the Centre National de Génotypage (CEA) based in Evry, and the Centre d'Etude du Polymorphisme Humain in Paris. It also involved the participation of researchers from a further 17 countries.

Lung cancer is the most common cause of cancer death worldwide with more than 1 million cases diagnosed annually. Before now, no common genetic variants that cause the disease had been identified. A two-stage approach was taken to detect DNA variants that are related to risk of lung cancer. First, the frequencies of more than 300,000 variants covering the whole genome were compared in 2000 lung cancer patients and a comparison group of 2500 people free of the disease. Then, DNA variants that showed marked differences in frequency were examined in another 2500 patients and 4500 controls to confirm their relationship with disease.

This two-stage approach led to the identification of one genomic region that contains DNA variants that are particularly common amongst patients compared to controls. People who carry these DNA variants in one copy (1 in 2 Europeans) are 30% more likely to develop lung cancer compared to those who do not have these variants. People who carry two copies of the variants (1 in 10 Europeans) are 80% more likely to develop lung cancer.

The small genomic region in which reside the lung cancer risk variants contains several genes that interact with nicotine and other tobacco toxins (nicotinic acetylcholine receptor genes). These genes are widely studied as possible actors in tobacco dependence and the receptors formed by these genes may increase the risk of lung cancer as they are found in the lung and are switched on by nicotine and known carcinogens found in tobacco smoke.

Over 80% of lung cancer is caused by tobacco smoking - and stopping smoking remains the most important method for preventing the disease. Even among those who quit however, the risk remains high and former smokers make up an increasing proportion of lung cancer patients, especially in countries where tobacco consumption has declined. The DNA variants identified in this study increase the risk of developing lung cancer in smokers and former smokers, and they may also increase risk in non-smokers. Present treatment strategies are limited, with only about 15% of patients surviving 5 years. Identifying genes that are involved in lung cancer may therefore help to identify treatment targets or allow for identification of individuals that are at high risk of disease in combination with smoking or other factors.

In addition to providing important insight into the relationship between lung cancer and nicotinic acetylcholine receptors, these findings also represent a powerful demonstration of the 'genome-wide analysis' approach to detecting new disease genes. It is likely that as more studies are conducted, and more groups combine their results, further lung cancer genes will be detected using this approach. The study also shows the importance of international collaboration in this new area of scientific research. In order to bring together a study large enough to find these genes, studies covering 16 European countries as well as Canada and the US were brought together.

Study author Paul Brennan from the International Agency for Research on Cancer in Lyon said, 'These results are particularly exciting as they provide the first identification of a major genetic factor that contributes to lung cancer risk. These findings will help us understand why lung cancer develops, and may indicate new strategies for treating the disease. They should not however detract from the main lung cancer message that people who do not smoke should not start and people who smoke should quit. Even those who do not have any copies of the risk gene have an important risk of developing lung cancer, as well as other tobacco related diseases'.

Author, Mark Lathrop, Director of the Centre d'Etude du Polymorphisme Humain and the Centre National de Génotypage, said that 'the biological mechanism by which these DNA variants affect the risk of lung cancer remains to be fully elucidated. Carcinogens may facilitate neoplastic transformation by stimulating angiogenesis and tumour growth mediated through their interaction with nicotinic acetylcholine receptors. The expression of these receptors can also be inhibited by nicotine receptor antagonists. If this mechanism is confirmed, it would most likely open new chemoprevention opportunities for lung cancer'.

The International Agency for Research on Cancer (IARC) is part of the World Health Organization. IARC's mission is to coordinate and conduct research on the causes of human cancer, the mechanisms of carcinogenesis, and to develop scientific strategies for cancer control. The Genetic Epidemiology Group within IARC conducts large scale case-control studies of specific cancers, and participates in international consortia, in order to ensure that studies have adequate sample size.